Summary Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adaptor protein that mediates a wide array of protein-protein interactions via its TRAF domain and a RING finger domain that possesses non-conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of IL-1 receptor (IL-1R)-mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the toll-like receptor (TLR) family, tumor growth factor-β receptors (TGFβR), and T cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor (IRF) pathways. In the context of the immune system, TRAF6-mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system, but also for maintaining immune tolerance, and more recent works have begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs.

Fatty acids (FA) are essential constituents of cell membranes, signaling molecules, and bioenergetic substrates. As CD8+ T cells undergo both functional and metabolic changes during activation and differentiation, dynamic changes in FA metabolism also occur. However, the contributions of de novo lipogenesis to acquisition and maintenance of CD8+ T cell function are unclear. Here, we demonstrate the role of FA synthesis in CD8+ T cell immunity. T cell-specific deletion of ACC1 (ACC1ΔT), an enzyme that catalyzes conversion of acetyl CoA to malonyl CoA, a carbon donor for long chain FA synthesis, resulted in impaired peripheral persistence and homeostatic proliferation of CD8+ T cells in naïve mice. Loss of ACC1 did not compromise effector CD8+ T cell differentiation upon listeria infection, but did result in a severe defect in Ag-specific CD8+ T cell accumulation due to increased death of proliferating cells. Furthermore, in vitro mitogenic stimulation demonstrated that defective ACC1ΔT CD8+ T cell blast and survival could be rescued by provision of exogenous FA. These results suggest an essential role for ACC1-mediated de novo lipogenesis as a regulator of CD8+ T cell expansion, and may provide insights for therapeutic targets for interventions in autoimmune diseases, cancer, and chronic infections.

Naïve T cell populations are maintained in the periphery at relatively constant levels via mechanisms that control expansion and contraction, and are associated with competition for homeostatic cytokines. It has been shown that in a lymphopenic environment naïve T cells undergo expansion due, at least in part, to additional availability of IL-7. We have previously found that T cell-intrinsic deletion of TRAF6 (TRAF6ΔT) in mice results in diminished peripheral CD8 T cell numbers. We now report that while naïve TRAF6ΔT CD8 T cells exhibit normal survival when transferred into a normal T cell pool, proliferation of naïve TRAF6ΔT CD8 T cells under lymphopenic conditions is defective. We identified IL-18 as a TRAF6-activating factor capable of enhancing lymphopenia-induced proliferation (LIP) in vivo, and that IL-18 synergizes with high dose IL-7 in a TRAF6-dependent manner to induce slow, LIP/homeostatic-like proliferation of naïve CD8 T cells in vitro. IL-7 and IL-18 act synergistically to upregulate expression of IL-18 receptor (IL-18R) genes, thereby enhancing IL-18 activity. In this context, IL-18R signaling increases PI3 kinase activation and was found to sensitize naïve CD8 T cells to a model non-cognate self-peptide ligand in a way that conventional costimulation via CD28 could not. We propose synergistic sensitization by IL-7 and IL-18 to self-peptide ligand may represent a novel costimulatory pathway for LIP.